What are the adverse drug reactions and drug‑drug interactions associated with duloxetine (Cymbalta)?

Duloxetine Adverse Drug Reactions and Drug-Drug Interactions

Duloxetine commonly causes nausea (occurring in 16-38% of patients), dry mouth, headache, constipation, dizziness, and fatigue, with nausea being dose-dependent and most prominent during the first week of treatment. 1, 2

Common Adverse Drug Reactions

Gastrointestinal Effects

• Nausea is the most frequent adverse effect, occurring in 37.8% of patients at 60 mg daily and 16.4% at 40 mg daily, typically most severe during initiation and dose escalation 2, 3
• Dry mouth, constipation, and diarrhea are common, consistent with serotonergic and noradrenergic mechanisms 1, 4
• These gastrointestinal symptoms usually diminish after the first 1-2 weeks but can persist at subtherapeutic doses 2

Neurological and Psychiatric Effects

• Dizziness, headache, and fatigue occur frequently, particularly during the first 1-2 weeks after initiation or dose changes 1, 2, 4
• Sedation and cognitive slowing can impair decision-making, clarity of thought, and reaction time, especially at low or subtherapeutic doses 2
• Insomnia and anxiety may paradoxically occur as initial adverse effects 1, 3

Cardiovascular Effects

• Duloxetine can increase systolic and diastolic blood pressure and heart rate, requiring monitoring during treatment 1, 2, 5
• Tachycardia has been reported, particularly in the first 6 weeks of therapy 6
• Use with caution in patients with cardiovascular comorbidities, especially when combined with NSAIDs 2

Other Common Effects

• Excessive sweating (hyperhidrosis) occurs with moderate to large frequency 1
• Decreased appetite and weight changes may occur 2
• Sexual side effects are common, similar to SSRIs 7
• Blurred vision can occur, though less commonly than with pregabalin or gabapentin 1

Withdrawal-Emergent Effects

• Discontinuation syndrome occurs when duloxetine is stopped abruptly or doses are missed, characterized by dizziness, fatigue, nausea, headache, irritability, anxiety, sensory disturbances (electric-shock sensations), and paresthesias 1, 2, 5
• Always taper duloxetine gradually over at least 2-4 weeks to minimize withdrawal symptoms, especially after treatment longer than 3 weeks 2, 5

Serious but Rare Adverse Reactions

Life-Threatening Complications

• Serotonin syndrome can occur, particularly when combined with other serotonergic agents (MAOIs, SSRIs, tramadol, meperidine, methadone, fentanyl, dextromethorphan) 1, 2, 5, 6
• Hepatic failure is a rare but serious risk; monitor for jaundice, dark urine, or right-upper-quadrant pain 2, 5
• Severe skin reactions have been reported 2, 5
• Suicidal thinking and behavior, particularly in children, adolescents, and young adults during the first few weeks of treatment 1, 2, 5

Metabolic and Hematologic

• Hyponatremia can occur, especially in older adults, presenting as severe fatigue with confusion, weakness, or memory problems 2

Cardiac

• QT prolongation is a concern when duloxetine is combined with other QT-prolonging drugs 1
• Worsening symptoms in patients with advanced heart failure have been reported 6

Drug-Drug Interactions

Contraindicated Combinations

• Monoamine oxidase inhibitors (MAOIs): Absolute contraindication due to risk of serotonin syndrome; allow at least 14 days between discontinuing an MAOI and starting duloxetine, and at least 5 days after stopping duloxetine before starting an MAOI 1, 5, 7, 8
• Potent CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin): Should be avoided as they can significantly increase duloxetine levels 2, 5, 8

High-Risk Combinations Requiring Caution

Serotonergic Agents

• Other antidepressants (SSRIs, SNRIs, TCAs): Increased risk of serotonin syndrome when combined 1, 6
• Opioids and pain medications (tramadol, meperidine, methadone, fentanyl): Additive serotonergic effects and increased sedation risk 1, 2
• Cough/cold medications (dextromethorphan, chlorpheniramine): Can contribute to serotonin syndrome 1
• Over-the-counter products (St. John's wort, L-tryptophan): Additive serotonergic effects 1
• Illicit drugs (ecstasy, methamphetamine, cocaine, LSD): Dangerous serotonergic interactions 1

When combining two serotonergic drugs, start the second agent at a low dose, increase slowly, and monitor closely for symptoms in the first 24-48 hours after dosage changes. 1

CYP450-Mediated Interactions

• Duloxetine is a moderate inhibitor of CYP2D6, requiring dose reductions and careful monitoring when combined with drugs metabolized by this pathway (e.g., certain antipsychotics, beta-blockers, antiarrhythmics) 2, 9, 5, 7, 8
• Duloxetine is metabolized by CYP1A2 and CYP2D6, making it vulnerable to interactions with inhibitors of these enzymes 2, 5, 8
• Duloxetine does not significantly inhibit CYP3A4, CYP1A2, CYP2C9, or CYP2C19, so interactions via these pathways are minimal 8

Cardiovascular Medications

• QT-prolonging drugs: Increased risk of cardiac arrhythmias when combined with duloxetine 1
• NSAIDs: Additive cardiovascular risk, particularly for blood pressure elevation; use with caution in patients with cardiovascular disease 1, 2

Other Notable Interactions

• Metoclopramide: Contraindicated with duloxetine use 6
• Benzodiazepines and antipsychotics: Commonly co-administered but require monitoring for additive sedation 6
• Cannabis/cannabinoids: Inhibit CYP1A2, potentially increasing duloxetine levels and risk of hepatotoxicity; start cannabis at the lowest dose, monitor liver enzymes, and watch for increased duloxetine effects 2

Monitoring Requirements

During Initiation and Dose Changes

• Monitor blood pressure and pulse regularly, as both can increase 2, 5
• Assess for nausea, sedation, and other adverse effects most prominent in the first 1-2 weeks 2
• Use standardized symptom rating scales to track treatment response 1

Ongoing Monitoring

• Liver function tests should be checked if using CBD-containing products or if signs of hepatotoxicity develop 2
• Monitor for signs of hyponatremia in older adults (confusion, weakness, memory problems) 2
• Assess for suicidal ideation, especially in the first few weeks of treatment in young patients 2, 5
• Watch for discontinuation syndrome if doses are missed or medication is stopped 1, 2

Special Populations

Older Adults

• Increased risk of cognitive impairment, falls, hyponatremia, and drug-drug interactions due to polypharmacy 2
• Require cautious dose escalation with small increments and longer observation periods (at least one week at each dose level) 2

Renal Impairment

• Duloxetine requires dosage adjustment in renal impairment and should be avoided in severe renal impairment 5

Pediatric Patients

• Approved for generalized anxiety disorder in children ≥7 years old 2, 9
• Parental oversight of medication regimens is paramount 1
• Monitor closely for suicidal thinking and behavior 2, 5

Clinical Pitfalls to Avoid

• Do not start duloxetine at 60 mg daily without a test dose: Begin at 30 mg for one week to reduce nausea and other adverse effects 2, 3
• Do not abruptly discontinue duloxetine: Always taper over at least 2-4 weeks to prevent withdrawal syndrome 2, 5
• Do not ignore subtherapeutic dosing: A 20 mg daily dose is below the therapeutic range and may cause persistent fatigue without clinical benefit; escalate to 60 mg daily for efficacy 2
• Do not combine with MAOIs or potent CYP1A2 inhibitors: These are contraindicated combinations 1, 5, 8
• Do not overlook cardiovascular monitoring: Blood pressure and pulse can increase, particularly when combined with NSAIDs 1, 2
• Do not assume all cannabis products are equivalent: THC content, CBD content, and formulation dramatically affect interaction potential with duloxetine 2